Transgenic animals are animals that carry an exogenous gene (transgene) in their genome, said gene having been introduced into germ cells of the animal, or into a predecessor thereof, at an early stage of development. The introduction of a transgene into the animal may have the aim of studying the behavior, expression or function of the gene introduced. Alternatively, the aim could be to genetically improve the affected individual for therapeutic ends or to improve the animal.
The generation of transgenic mammals is well established (see for example, Hogan, Constantini & Lacy (1986), “Manipulating the Mouse Embryo. A Laboratory Manual”, Cold Spring Harbor Laboratory, Cold Spring Harbor (1986)) and proof of this is the high number of articles and patents that describe transgenic mammals. By way of illustration, the U.S. Pat. Nos. 4,736,866, 4,873,191, 5,175,383 and 5,175,384 can be cited.
The expression of a transgene can confer a new phenotype on the mammal. Depending on the transgene inserted and its level of expression in the mammal, the animal can be made to be more or less susceptible to a given disease. Such transgenic mammals are valuable models for the in vivo study of compounds that could potentially be useful in the treatment or prevention of said disease, and/or in the development of useful methods for the diagnosis of said disease.
The term “human pathology of stem cell origin” includes a group of human diseases, both neoplastic and non-neoplastic, that are of both hematopoietic and non-hematopoietic stem cell origin, for example, myeloid leukemias, B-cell lymphoid leukemias, T-cell lymphoid leukemias, lymphomas, sarcomas and pathologies of stem cell development, for example, congenital immunodeficiency, and Fanconi anemia, etc. Malignant neoplastic pathology (which is almost entirely of stem cell origin) is currently treated in human beings by a combination of strategies of chemotherapy, radiotherapy and/or surgery; strategies that do not discriminate between normal cells and tumor cells. Therapeutic treatment of non-neoplastic pathology is performed by substitutive therapies (immunoglobulins, vaccines, transfusions, etc.).
In recent years, activated genes and/or genes generated by chromosomal anomalies associated with both hematopoietic tumors and solid tumors have been identified [Annu. Rev. Genetics (1997) 31: 429-453]. Despite being identified, there are currently no animal models that reproduce said pathology [Oncogene (1999) 18: 5248; Oncogene (1999) 18: 5249-5252], though it has been shown that said genes are tumorigenic in vivo [Current Genomics (2000), 1:71-80]. Similarly, recently it has been shown that the target where the cancer is initiated is a stem cell [Blood (2000), 95:1007-1113; Oncogene (2000) 19(20): 2413-2422; Nature (2001) 414; 105-111].
In Current Genomics (2000), 1:71-80, some known mouse models are mentioned that express genes or gene fusions that are activated by chromosomal anomalies associated with different pathologies, for example, chronic myeloid leukemia (BCR-ABLp210); B-cell acute lymphoblastic leukemia (BCR-ABLp190), B-cell acute lymphoblastic leukemia (HOX11, RHOM2/LMO-2 and TAL1), etc. However, said models have only shown that the proteins expressed by said genes or gene fusions are tumorigenic, but they have not specifically reproduced the human pathology with which they are associated.
In view of the devastating effects of human pathologies of stem cell origin, there is a need to develop appropriate animals that provide an in vivo model for studying said human pathology as well as potentially useful compounds in the treatment and/or prevention of said pathology.